Farnesoid X Receptor (FXR, NR1H4) belongs to nuclear receptor superfamily and is a key metabolic regulator in liver metabolism, including bile acid (BA), lipid and glucose metabolism. We recently demonstrated that FXR-/- mice spontaneously developed liver tumors as they aged and the mice displayed prominent liver injury, inflammation and irregular regeneration. These results suggest a novel role of FXR in suppressing hepatocellular carcinoma (HCC). HCC remains a major cause of cancer death worldwide, and the incidence of HCC in developed countries, including the United States, is increasing. Although there are several animal models of HCC, FXR-/- mice provide a unique pathologically relevant model to study the mechanism of HCC development, especially the etiological connection between liver metabolism and hepatocarcinogenesis. The development of HCC in FXR-/- mice mimics the pathological progression of human HCC, therefore, better understanding the roles of FXR in HCC will help us to identify new targets and provide novel approaches for HCC prevention and therapy. Based on our previous work and more preliminary data accompanying this proposal, we hypothesize that FXR is a novel liver protector and HCC suppressor. Specifically, FXR regulates the expression of a superoxide dismutase (EC-SOD, SOD3) and other anti-oxidative stress genes that suppress the deleterious effect of reactive oxygen species (ROS) and prevents prolonged JNK1 activation in liver. FXR also directly modulates the expression of genes in anti-apoptosis pathways, and that dysfunction of FXR results in enhanced cell death and liver injury, thereby promoting the HCC development. We propose two Specific Aims in this proposal. In the first Aim, we will define the roles of FXR in ROS metabolism and JNK1 activation and their link to HCC development. In the second Aim, we will determine the roles of FXR in regulating the expression of anti-apoptotic genes. These experimental approaches will help us better understand the roles of FXR in HCC and provide insight into the human hepatocarcinogenesis. The proposed work is innovative as the proposed studies will define a novel link between liver metabolism and HCC. Successful completion of the proposed studies will lead to the development of novel approaches for the prevention and treatment of HCC. PUBLIC HEALTH RELEVANCE: We propose to investigate the role of a key liver metabolic regulator, Farnesoid X Receptor (FXR), in HCC development. Results from these studies will not only provide insight into an etiological connection between liver metabolism and HCC but also help us develop novel approaches for the prevention and treatment of human HCC.